Diagnostic Accuracy of Point-of-Care Fecal Calprotectin and Immunochemical Occult Blood Tests for Diagnosis of Organic Bowel Disease in Primary Care: The Cost-Effectiveness of a Decision Rule for Abdominal Complaints in Primary Care (CEDAR) Study L. Kok, S.G. Elias, B.J.M. Witteman, J.G. Goedhard, J.W.M. Muris, K.G.M. Moons, and N.J. de Wit June © Copyright 2012 by the American Association for Clinical Chemistry

© Copyright 2009 by the American Association for Clinical Chemistry Introduction  Lower abdominal complaints are common in primary care  Organic bowel disease (OBD) is rare: -Colorectal cancer, advanced adenomatous polyps - Inflammatory bowel disease (IBD)  Symptoms of OBD overlap with benign and functional bowel disorders  Diagnostic challenge for the general practitioner (GP)  Fear of missing OBD results in many referrals for colonoscopy  Colonoscopy is invasive, costly and a scarce resource

© Copyright 2009 by the American Association for Clinical Chemistry Introduction  Simple, non-invasive tests are needed  Fecal biomarker tests have received much interest  Editorial C.G. Fraser et al, Clin Chem June 2012  E.g. calprotectin and iFOB tests  Point-of-care tests have advantages in this setting  But there are also drawbacks

© Copyright 2009 by the American Association for Clinical Chemistry Question 1  Why is referring all patients with persistent lower abdominal complaints for colonoscopy not desirable?

© Copyright 2009 by the American Association for Clinical Chemistry Materials and Methods  Cross-sectional diagnostic study in primary care  Study population:  386 Dutch patients with lower abdominal complaints >2 wks (suggestive for OBD) who were referred for colonoscopy by their GP  Index tests:  Calprotectin point-of-care test and ELISA test  Point-of-care iFOBT  Reference standard:  Colonoscopy with histology if needed

© Copyright 2009 by the American Association for Clinical Chemistry Materials and Methods  Primary endpoint, OBD defined as:  Colorectal cancer, all adenomas, IBD, diverticulitis  Non-OBD: all other findings  Secondary endpoint, OBD defined as:  Colorectal cancer, advanced adenomas (>1 cm), IBD, diverticulitis  Non-OBD: all other findings (including small adenomas)  Data analysis:  Diagnostic estimates according to manufacturer’s cutoffs, AUCs

© Copyright 2009 by the American Association for Clinical Chemistry Question 2  Which conditions that can be found at colonoscopy will have increased calprotectin concentrations and which may be detected by the iFOBT?

© Copyright 2009 by the American Association for Clinical Chemistry Definitive diagnoses a Table 1. Definitive diagnoses in the 386 Dutch primary care patients with persistent lower abdominal complaints who were referred for colonoscopy by their GP. a Sums may not total 100% due to rounding. b One patient was diagnosed with microscopic colitis, 1 with lymphocytic colitis, and 4 with nonspecific colitis. c Of the 4 patients with proctitis, 1 was diagnosed with radiation proctitis.

© Copyright 2009 by the American Association for Clinical Chemistry Main results Table 2. Diagnostic accuracy of calprotectin and iFOB POC test and calprotectin ELISA, with and without advanced adenomas classified as OBD. a Combination of the calprotectin and iFOB POC tests. The combination is positive if 1 of the 2 tests is positive and negative if both tests are negative.

© Copyright 2009 by the American Association for Clinical Chemistry Figure 1. ROC curves and AUCs for the calprotectin ELISA and POC test, for the 2 endpoints. (A), Calprotectin ELISA test with primary endpoint (adenocarcinoma, IBD, diverticulitis and all adenomas classified as OBD). (B), Calprotectin POC test with primary endpoint. (C), Calprotectin ELISA test with secondary endpoint (adenocarcinoma, IBD, diverticulitis and only advanced (>1 cm) adenomas classified as OBD). (D), Calprotectin POC test with secondary endpoint. Main Results

© Copyright 2009 by the American Association for Clinical Chemistry Questions 3 & 4  Which diagnostic estimate is very important in the primary care setting and why?  Sensitivity  Negative predictive value (NPV)  Diagnostic odds ratio (dOR)  How could this estimate be improved so that OBD will not be missed?

© Copyright 2009 by the American Association for Clinical Chemistry Conclusions  Overall test performance depended on the size of adenomas  When small adenomas were considered OBD  Diagnostic accuracy of all tests was insufficient  When only advanced adenomas were considered OBD  All tests were able to rule out OBD to a reasonable extent  Best results when POC tests were combined

© Copyright 2009 by the American Association for Clinical Chemistry Conclusions  A new strategy could be to use the combined POC tests  Patients with both tests negative would then not need referral  This would reduce the number of referrals for colonoscopy  However, 5% of CRC and 10% of IBD cases would have been missed  Approaches to improve this strategy are needed  E.g. use in combination with scoring systems  Development of optimal cutoffs  Editorial C.G. Fraser et al

© Copyright 2009 by the American Association for Clinical Chemistry EDITORIAL SLIDE  Professionals in laboratory medicine should:  Encourage ALL users of guaiac fecal occult blood tests to replace these fecal tests with the more effective fecal immunochemical tests for hemoglobin  Participate in the development and evaluation of better automated fecal tests for calprotectin and hemoglobin  Assist in selection of fecal tests and in ensuring correct use – from sample collection to the reporting of results  Play pivotal roles in studies using fecal tests for investigation of patients with lower abdominal symptoms  Encourage adherence to STARD guidelines and ensure that study descriptions and data presentations fulfill recent recommendations

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